PT  - JOURNAL ARTICLE
AU  - Seithel, Annick
AU  - Eberl, Sonja
AU  - Singer, Katrin
AU  - Auge, Daniel
AU  - Heinkele, Georg
AU  - Wolf, Nadine B.
AU  - Dörje, Frank
AU  - Fromm, Martin F.
AU  - König, Jörg
TI  - The Influence of Macrolide Antibiotics on the Uptake of Organic Anions and Drugs Mediated by OATP1B1 and OATP1B3
AID  - 10.1124/dmd.106.014407
DP  - 2007 May 01
TA  - Drug Metabolism and Disposition
PG  - 779--786
VI  - 35
IP  - 5
4099  - http://dmd.aspetjournals.org/content/35/5/779.short
4100  - http://dmd.aspetjournals.org/content/35/5/779.full
SO  - Drug Metab Dispos2007 May 01; 35
AB  - Macrolides may cause severe drug interactions due to the inhibition of metabolizing enzymes. Transporter-mediated uptake of drugs into cells [e.g., by members of the human organic anion transporting polypeptide (OATP) family] is a determinant of drug disposition and a prerequisite for subsequent metabolism. However whether macrolides are also inhibitors of uptake transporters, thereby providing an additional mechanism of drug interactions, has not been systematically studied. The human OATP family members OATP1B1 and OATP1B3 mediate the uptake of endogenous substances and drugs such as antibiotics and HMG-CoA reductase inhibitors (statins) into hepatocytes. In this study we investigated the potential role of these uptake transporters on macrolide-induced drug interactions. By using sulfobromophthalein (BSP) and the HMG-CoA reductase inhibitor pravastatin as substrates, the effects of the macrolides azithromycin, clarithromycin, erythromycin, and roxithromycin and of the ketolide telithromycin on the OATP1B1- and OATP1B3-mediated uptake were analyzed. These experiments demonstrated that the OATP1B1- and OATP1B3-mediated uptake of BSP and pravastatin can be inhibited by increasing concentrations of all macrolides except azithromycin. The IC50 values for the inhibition of OATP1B3-mediated BSP uptake were 11 μM for telithromycin, 32 μM for clarithromycin, 34 μM for erythromycin, and 37 μM for roxithromycin. These IC50 values were lower than the IC50 values for inhibition of OATP1B1-mediated BSP uptake (96–217 μM). These macrolides also inhibited in a concentration-dependent manner the OATP1B1- and OATP1B3-mediated uptake of pravastatin. In summary, these results indicate that alterations of uptake transporter function by certain macrolides/ketolides have to be considered as a potential additional mechanism underlying drug-drug interactions. The American Society for Pharmacology and Experimental Therapeutics